Benzimidazole derivatives, processes for preparing them and...

Details Benzimidazole derivatives, processes for preparing them and... Benzimidazole derivatives, processes for preparing them and...

2002-02-06

2003-12-02

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S199000

Reexamination Certificate

active

06656956

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to benzimidazole derivatives of formula (I)
wherein the groups X, R
1
, R
2
, R
3
and R
4
may have the meanings given in the claims and specification, processes for preparing them and the use of benzimidazole derivatives as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting activity.
BACKGROUND TO THE INVENTION
Benzimidazole derivatives are known from the prior art as active substances having valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles which can be used to good effect for the prevention and treatment of venous and arterial thrombotic diseases, on the basis of their thrombin-inhibiting activity.
In contrast to the use of benzimidazole derivatives as described above and known from the prior art, the aim of the present invention is to prepare new tryptase-inhibitors which can be used, on the basis of their tryptase-inhibiting properties, for the prevention and treatment of inflammatory and/or allergic diseases.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide benzimidazole derivatives of formula (I)
wherein the groups X, R
1
, R
2
, R
3
and R
4
may have the meanings given in the claims and specification, processes for preparing them and the use of benzimidazole derivatives as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting activity.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that benzimidazole derivatives of general formula (I) wherein the groups R
1
, R
2
, R
3
and R
4
may have the meanings given hereinafter have a tryptase-inhibiting effect and may be used according to the invention for the prevention and treatment of diseases in which tryptase-inhibitors may develop a therapeutic benefit.
The present invention thus relates to benzimidazole derivatives of formula (I)
wherein
R
1
denotes a group selected from among C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl and C
2
-C
12
-alkynyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, CF
3
, phenoxy, COOH, halogen, —CO(C
1
-C
12
-alkoxy), —CO—NR
5
R
6
, —NR
5
R
6
or C
1
-C
1
2-alkoxy-phenoxy, or phenyl-C
1
-C
12
-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
12
-alkoxy, carboxy, halogen, C
1
-C
12
-alkoxycarbonyl or CF
3
, or
 a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C
1
-C
12
-alkylene bridge, which may contain one or two heteroatoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C
1
-C
12
-alkyl or benzyl;
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes a hydrogen atom or a C
1
-C
12
-alkyl group which may optionally be mono- or disubstituted by one or two groups selected from among —COOH, —COO—C
1-6
-alkyl, furanyl, benzofuranyl, thiophenyl, benzothiophenyl, anthracenyl, phenyl, pyridyl and naphthyl, while the abovementioned aromatic and heteroaromatic substituents in turn may each be mono-, di- or trisubstituted by one or more of the groups selected from among C
1
-C
12
-alkyl, C
1
-C
12
-alkoxy, halogen, —C
1
-C
12
-alkyl-halogen, —NH
2
, —NH(C
1
-C
12
-alkyl), —N(C
1
-C
12
-alkyl)
2
, NO
2
, hydroxy, —CF
3
, —NHCO—C
1
-C
12
-alkyl, —COOH, —COO(C
1
-C
12
-alkyl), —CONH
2
, —CONH(C
1
-C
12
-alkyl), —CON(C
1
-C
12
-alkyl)
2
, —CONH(C
1
-C
12
-alkyl)-COO(C
1
-C
12
-alkyl) and phenyl-C
1
-C
12
-alkyl;
X denotes >C═O, >CH
2
or —CH
2
CH
2
—;
R
4
denotes a group of formula (A)
W denotes N or CH;
A denotes NR
6
when n=0, and denotes O, CHR
6
or NR
6
when n=1;
R
5
and R
6
independently of one another each denote a hydrogen atom or a group of formula
—B—(CO)
m
—,
wherein
B denotes a C
1
-C
12
-alkyl, C
3
-C
8
-cycloalkyl, phenyl, naphthyl or a fluorenyl group or a 5- or 6-membered heterocyclic group containing nitrogen, oxygen and/or sulphur, wherein the group B may optionally be substituted in each case by one or more groups selected from among halogen, halo-C
1
-C
12
-alkyl, halo-C
1
-C
12
-alkoxy, —OH, C
1
-C
12
-alkyl, C
1
-C
12
-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, —CO—O—H, —CO—O—C
1
-C
12
-alkyl, —NO
2
, pyrrolidin-1-yl, piperidin-1-yl, —NH
2
, —NH—C
1
-C
12
-alkyl, —NH-phenyl, —NH-pyridyl, —N(C
1
-C
12
-alkyl)
2
and —C(═NH)NH
2
, and
m denotes 0 or 1, or
R
5
and R
6
together with the nitrogen atom attached form a 5- to 8-membered heterocyclic group, which may be substituted by a group selected from among halogen, halo-C
1
-C
12
-alkyl, —OH, —C
1
-C
12
-alkyl, C
1
-C
12
-alkoxy, phenoxy, benzyloxy, —CO—O—C
1
-C
12
-alkyl, —NO
2
, phenyl, pyrrolidin-1-yl, piperidin-1-yl, —NH
2
, —NH—C
1
-C
12
-alkyl, —NH-pyridyl, —N(C
1
-C
12
-alkyl)
2
and —C(═NH)NH
2
,
n is 0 or 1;
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The term alkyl groups (including those which are part of other groups, especially alkoxy), unless otherwise stated, denotes branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, most preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Examples are: methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. Unless otherwise stated, the above terms propyl, butyl, pentyl or hexyl also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl etc.
The term haloalkyl groups (including those which are part of other groups, especially haloalkoxy), unless otherwise stated, denotes branched and unbranched haloalkyl groups with 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, which are substituted by at least one halogen atom, particularly fluorine atom. Fluorinated groups of the formula
—(CH
2
)
p
—(CF
2
)
q
—Y
wherein
p denotes 0 or an integer from 1 to 4,
q denotes an integer from 1 to 4, and
Y denotes hydrogen or fluorine, are preferred.
Examples include: trifluoromethyl, trifluoromethoxy, difluoromethoxy, perfluoroethyl, perfluoropropyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1,1,1-trifluoroprop-2-yl, etc.
The term alkenyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms, provided that they have at least one double bond, for example the alkyl groups mentioned above as well, provided that they have at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are formed), propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.
The term alkynyl groups (including those which are part of other groups) denotes alkynyl groups having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms provided that they have at least one triple bond, e.g. ethynyl, propargyl, butynyl, pentynyl and hexynyl.
The term halogen generally denotes fluorine, chlorine, bromine or iodine.
The term “5- or 6-membered heterocyclic group containing nitrogen, oxygen and/or sulphur” as used in connection with the group B, generally denotes an aromatic or saturated group having 5 or 6 cyclic atoms, wherein at least one cyclic atom is a heteroatom selected from among N, O and S, which may optionally be fused to another cyclic system.
The term “5- to 8-membered heterocyclic group” as used for the group formed by R
5
and R
6
together with the enclosed nitrogen atom, generally denotes a saturated nitrog

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